...STANFORD Calif. Investigators at the Stanford University School of ...The new technique also could help to speed the development of therapie...The procedure described in a Nature Medicine paper to be publi... We have yet to find a protein the system doesn't work with said s...

STANFORD, Calif. Investigators at the Stanford University School of
Medicine have found a way to quickly and reversibly fine-tune the
activity of individual proteins in cells and living mammals, providing a
powerful new laboratory tool for identifying more precisely than ever
before the functions of different proteins.

The new technique also could help to speed the development of therapies
in which cancer-fighting proteins are selectively delivered to tumors.

The procedure, described in a Nature Medicine paper to be published
online Sept. 28, appears to be broadly applicable to efforts to
understand the biological roles of all kinds of proteins, including
those that are secreted by cells. This category includes many potent
intercellular signaling proteins that can influence the immune system,
for example by attracting its attention to an existing tumor.

"We have yet to find a protein the system doesn't work with," said
senior author Steve Thorne, PhD, an assistant professor at the
University of Pittsburgh who was involved in the work while a research
associate at Stanford. The work was conducted under the direction of
Chris Contag, PhD, associate professor of pediatrics, of radiology and
of microbiology and immunology; and Tom Wandless, PhD, assistant
professor of chemical and systems biology.

This technique, which was tested in mice, involves pairing specially
bioengineered proteins with a drug, aptly named Shield-1, that prevents
the proteins from being degraded.

This approach stands in contrast to current ways of learning about
proteins' functions, which are largely based on impeding a cell's
production of the protein. Unfortunately, that cellular process can be
slow and cumbersome, meaning that scientists get a sluggish response to
such manipulations. In addition, current methods to perturb protein
function are either irreversible once a protein's production is
knocked out, it can't be turned back on or difficult to execute.

The new technique, instead, influences the level of speed with which the
protein is broken downa much faster process than its production.
Moreover, it is reversible and works like a dimmer switch for an
overhead light. The rate of a protein's degradation and, thus, the
level of its biological activity can be increased or decreased by
supplying more or less of Shield-1, permitting scientists to study the
biological effects of slightly increasing or diminishing a protein's
activity inside a cell over short time frames: for example, during a
particular period in an organism's development.

The Stanford team succeeded in controlling levels of proteins by a
relatively simple method pioneered by Wandless and his then-graduate
student, Laura Banaszynski, PhD. They created special, bioengineered
versions of several different proteins, in each case altering the
protein by adding a small extra piece that didn't interfere with its
biological function, but flagged it for rapid degradation. This
degradation can be halted in its tracks, however, by Shield-1, which
binds to the bioengineered protein, shielding it from destruction by the
cell's breakdown machinery. The drug thus can enhance the bioengineered
protein's intracellular concentration and activity; withdrawing the drug
has the opposite effect.

"The process is tunable, and fast. As soon as you remove the drug, you
affect the degradation time of the protein," said Mark Sellmyer, a
graduate student at the School of Medicine, who shares lead authorship
of the study with Banaszynski.

The degradation-vulnerable bioengineered proteins were each produced by
attaching the gene coding for a protein to another DNA sequence coding
for the small extra piece that flags the protein for rapid degradation.
The scientists then inserted the altered gene into a virus capable of
infecting cells and introducing the altered gene into the cells' genomes.

In experiments demonstrating for the first time that the new technique
can be used to effectively regulate a physiologically active protein in
live mice, cultured tumor cells were grafted under the skin of
immunologically impaired mice. As expected, the mice developed numerous
tumors. The investigators had altered these cultured tumor cells so that
they produced a degradation-prone bioengineered version of the protein
IL-2 that, when secreted by cells, sends potent signals drawing the
immune system's attention to those cells. When these altered tumor cells
were grafted subcutaneously in the absence of Shield-1, the tumors grew
just as before.

But if the tumor cells were first pretreated with Shield-1 they secreted
IL-2, preventing any initial tumor growth. If Shield-1 was withheld at
first and then administered to the mice five days after the grafts,
tumors that had developed in those first few days regressed. By day 14,
the tumors were gone.

Another set of experiments employed a mutant virus that had been
previously developed by Thorne as a cancer therapy. The investigators
inserted the gene for a bioengineered, degradation-prone form of a
cell-killing protein into the specialized virus. They then administered
it intravenously to live, tumor-bearing mice. When no Shield-1 was
provided, the tumor growth was only slightly diminished. But if Shield-1
was supplied three days after infection, when the virus had established
a solid foothold in the tumors but been cleared from normal cells,
tumors were completely eradicated in 90 percent of the mice. Meanwhile,
normal cells were spared the substance's lethal effects.

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